PB2176: AN AUSTRALIAN/NEW ZEALAND RANDOMIZED TRIAL OF POST-TRANSPLANT CYCLOPHOSPHAMIDE IN MATCHED RELATED PERIPHERAL BLOOD STEM CELL TRANSPLANTS FOR ACUTE LEUKAEMIA OR MYELODYSPLASIA – ALLG BM12
Authors: D. Curtis, S. Patil, D. Purtill, D. Ritchie, D. Yeung, C. Lewis, E. Wong, J. Moore, T. Perera, M. King, R. De Abreu Lourenco, O. Morrissey, G. Hill, J. Reynolds, S. Tey, D. Gottlieb
Journal: HemaSphere (2022)

Background: Graft versus host disease (GVHD) remains a major clinical problem in allogeneic peripheral blood stem cell (PBSC) transplantation, even when matched-siblings are used as donors. The cumulative risk of clinically significant acute (grade III-IV) and chronic (moderate-severe) GVHD is 40% after PBSC matched-sibling transplant with calcineurin inhibitor-based prophylaxis. Post-transplant cyclophosphamide (PTCy) is increasingly used for matched-sibling PBSC transplants despite the absence of randomized data. While retrospective data suggest PTCy show low rates of chronic GVHD, potential disadvantages of PTCy include increased risks of CMV reactivation, veno-occlusive disease (VOD), haemorrhagic cystitis and exposure of donor haematopoiesis to high-dose alkylator resulting in DNA damage and potential for secondary myeloid neoplasia. Finally, PTCy may suppress graft-versus-leukemia effects in the setting of matched donor cells, potentially increasing the risk of relapse. Therefore, randomized trials are needed before widespread use in the matched-sibling setting can be recommended. The randomised BMT CTN 1703 study comparing Tacrolimus and Methotrexate (MTX) to PTCy/Tacrolimus and MMF is ongoing but does not include myeloablative conditioning (MAC) regimens. Aims: Perform a prospective randomized trial to compare PTCy with calcineurin inhibitor-based GVHD prophylaxis in matched-sibling PBSC transplants for acute leukemia in CR or MDS. Methods: The BM12 Australasian Leukaemia Lymphoma Group (ALLG) trial (ACTRN12618000505202) funded by the Australian Government Medical Research Future Fund (APP1152188) will randomize 134 adult patients with acute leukemia or MDS to either conventional GVHD prophylaxis (CsA and MTX) or PTCy (50 mg/kg) on Days +3 and +4 followed by CsA from Day +5. Both MAC and reduced intensity conditioning (RIC) regimens are allowed. Regimens are the same across the two arms apart from TBI-based MAC, where there was lack of safety data for the use of PTCy following CyTBI. In this setting, Fludarabine plus TBI is used for the PTCy arm. The primary endpoint is GVHD and relapse free survival (GRFS), with GVHD defined as grade 3 or greater acute GVHD and NIH-defined moderate or severe chronic GVHD. The study has an 80% power for a 2-sided log-rank test (a=0.05) to detect a hazard ratio of 0.54, which corresponds to 24-month GRFS of 28% and 50% in the two arms. Analysis of the primary endpoint (GRFS) will take place after 86 events are known to have occurred. An interim analysis (IA), to enable consideration of early stopping either for overwhelming evidence of an efficacy difference or for futility, will take place when approximately half of the quota of 86 events has occurred. Secondary endpoints include engraftment, rates of acute and chronic GVHD, relapse, non-relapse mortality, overall survival, VOD, quality of life and health economic impact. Correlative studies include impact of PTCy on measurable residual disease, immune activation, immune reconstitution and CMV immunity. Results: The trial is open at 8 Australian and 2 New Zealand sites, with 73 patients randomised up to 5th January 2022. Early stopping rules for unexpectedly high rates of non-relapse mortality, VOD, haemorrhagic cystitis and engraftment failure in the first 30 patients in either arm have to date not been triggered. Recruitment is expected to be completed in 2023. Summary/Conclusion: This prospective randomized trial will provide evidence for the use of PTCy for GVHD prophylaxis in matched-sibling PBSC transplants for acute leukemia in CR and MDS.